This project aims to utilize the unique resources of the Human Neurobiology Core Brain Bank to investigate further our hypothesis of behavior disinhibition, mediated by deficits in the ventrolateral prefrontal cortex, that lead to suicidal behavior. Project 2A (Ventral Prefrontal Cortex) has four components: (1) systematic cytoarchitectonic investigation of ventrolateral and dorsal prefrontal cortex of suicides and controls, to determine neuron density. This serves as an index to be able to obtain correlations with the numbers of brainstem serotonergic and noradrenergic source neurons, as well as with receptor density measures in the brainstem and cortex; (2) Association studies of candidate genes with suicide and central serotonin function (Assays will be done by the Clinical Laboratory Core); (3) Development and application of microarray technology to analyze gene expression in brain areas of interest of depressed and non-depressed suicides, depressed and non- depressed non-suicides (Assays will be done by the Clinical Laboratory Core); and (4) 5-HT/2C receptor pre-mRNA editing in suicide victims (depressed and non-depressed) and normal controls, followed by 5- HT/2A/2C receptor agonist-promoted binding of 35S-GTPgammaS in membrane homogenates. Project 2B proposes a series of gene expression studies in the serotonergic DRN of suicide victims and depressed and non-depressed controls, including the serotonin transporter, 5-HT1A receptor, tryptophan hydroxylase and select transcription factors (e.g. pCREB). Alcoholics represent a high-risk population for suicide and Project 2C proposes to study the serotonergic neurons of alcoholic suicides, alcoholic non-suicides and controls by immunocytochemistry and immunoautoradiography. The proposed cytoarchitectonic and molecular biological approaches aim to identify possible sites of abnormality in the brainstem and cortex of four groups; suicide victims, non-psychiatric non-suicide controls, and two other non-suicide control groups: depressed and alcoholics.